Methods for treating gastro-esophageal reflux disease and other disorders associated with the digestive tract using optically pure (+) cisapride

ABSTRACT

Methods are disclosed utilizing the optically pure (+) isomer of cisapride. This compound is useful in treating emesis while substantially reducing adverse effects associated with racemic cisapride.

This application is a continuation-in-part of application Ser. No.07/909,841, filed Jul. 7, 1992, now abandoned.

TECHNICAL FIELD

This invention relates to novel compositions of matter containingoptically pure (+) cisapride. These compositions possess potent activityin treating gastro-esophageal reflux disease while substantiallyreducing adverse effects associated with the administration of theracemic mixture of cisapride including but not limited to diarrhea,abdominal cramping and elevations of blood pressure and heart rate.Additionally, these novel compositions of matter containing opticallypure (+) cisapride are useful in treating emesis and such otherconditions as may be related to the activity of (+) cisapride as aprokinetic agent, including but not limited to dyspepsia, gastroparesis,constipation, and intestinal pseudo-obstruction, while substantiallyreducing adverse effects associated with the administration of theracemic mixture of cisapride. Also disclosed are methods for treatingthe above-described conditions in a human while substantially reducingadverse effects that are associated with the racemic mixture ofcisapride, by administering the (+) isomer of cisapride to a human inneed of such treatment.

The active compound of these compositions and methods is an opticalisomer of racemic cis-cisapride, which is described in European PatentApplication No. 0,076,530 A2 published Apr. 13, 1983 and U.S. Pat. Nos.4,962, 115 and 5,057,525. Chemically, the active compound, of thepresently disclosed compositions and methods, is the (+) isomer ofcis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide, hereinafterreferred to as (+) eisapride. The term "(+) isomer of cisapride" andparticularly the term "(+) cisapride" encompass optically pure andsubstantially optically pure (+) cisapride. Similarly, as used herein,the terms "racemic cisapride" or "racemic mixture of cisapride" refer tothe cis diastereomeric racemate.

Cisapride, which is the subject of the present invention, is availablecommercially only as the 1:1 racemic mixture of the cis diastereomericracemate. Cisapride is available only as a mixture of optical isomers,called enantiomers, i.e., a mixture of cis(+) and cis(-) cisapride.

BACKGROUND OF THE INVENTION Steric Relationship and Drug Action

Many organic compounds exist in optically active forms, i.e., they havethe ability to rotate the plane of plane-polarized light. In describingan optically active compound, the prefixes D and L or R and S are usedto denote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (-) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (-)or 1 meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they aremirror images of one another. A specific stereoisomer may also bereferred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric or racemic mixture.

Stereochemical purity is of importance in the field of pharmaceuticals,where 12 of the 20 most prescribed drugs exhibit chirality. A case inpoint is provided by the L-form of the beta-adrenergic blocking agent,propranolol, which is known to be 100 times more potent than theD-enantiomer.

Furthermore, optical purity is important since certain isomers mayactually be deleterious rather than simply inert. For example, it hasbeen suggested that the D-enantiomer of thalidomide was a safe andeffective sedative when prescribed for the control of morning sicknessduring pregnancy, while the corresponding L-enantiomer has been believedto be a potent teratogen.

Pharmacologic Action

U.S. Pat. Nos. 4,962,115 and 5,057,525 (collectively "Van Daele")disclose N-(3-hydroxy-4-piperidenyl)benzamides including the cis andtrans diastereomeric racemates of cisapride. Van Daele discloses thatthese compounds, the pharmaceutically acceptable acid addition saltsthereof and the stereochemically isomeric forms thereof, stimulate themotility of the gastro-intestinal system. Van Daele states that thediastereomeric racemates of these compounds may be obtained separatelyby conventional methods and that these diastereomeric racemates may befurther resolved into their optical isomers. Van Daele also reports the"lowest effective concentration . . . whereby a significant stimulationof the acetylcholine release is noted", for cis(+) and cis(-) cisapride,to be 0.01 mg/L and 0.04 mg/L respectively, while the "lowest effectivedose whereby antagonistic effects of dopamine-induced gastric relaxationare observed" is reported to be 0.63 mg/L for both cis(+) and cis(-)cisapride. Therefore, Van Daele teaches that cis(+) and cis(-) cisapridehave roughly identical pharmacological profiles.

Cisapride is one of a class of compounds known as benzamide derivatives,the parent compound of which is metoclopramide (See: Schapira et al.,Acta Gastro-Enterolog. Belg. LIII: 446-457, 1990). As a class, thesebenzamide derivatives have several prominent pharmacological actions.The prominent pharmacological activities of the benzamide derivativesare due to their effects on the neuronal systems which are modulated bythe neurotransmitter serotonin. The role of serotonin, and thus thepharmacology of the benzamide derivatives, has been broadly implicatedin a variety of conditions for many years (See Phillis, J. W., "ThePharmacology of Synapses", Pergamon Press, Monograph 43, 1970; Frazer,A. et al., Annual Rev. of Pharmacology and Therapeutics 30: 307-348,1990). Thus, research has focused on locating the production and storagesites of serotonin as well as the location of serotonin receptors in thehuman body in order to determine the connection between these sites andvarious disease states or conditions.

In this regard, it was discovered that a major site of production andstorage of serotonin is the enterochromaffin cell of thegastrointestinal mucosa. It was also discovered that serotonin has apowerful stimulating action on intestinal motility by stimulatingintestinal smooth muscle, speeding intestinal transit, and decreasingabsorption time, as in diarrhea. This stimulating action is alsoassociated with nausea and vomiting.

Because of their modulation of the serotonin neuronal system in thegastrointestinal tract, many of the benzamide derivatives are effectiveantiemetic agents and are commonly used to control vomiting duringcancer chemotherapy or radiotherapy, especially when highly emetogeniccompounds such as cisplatin are used (See: Costall et al.,Neuropharmacology 26: 1321-1326, 1987). This action is almost certainlythe result of the ability of the compounds to block the actions ofserotonin (5HT) at specific sites of action, called the 5HT3-receptor,which was classically designated in the scientific literature as theserotonin M-receptor (See: Clarke et al., Trends in PharmacologicalSciences 10: 385-386, 1989). Chemo- and radio-therapy may induce nauseaand vomiting by the release of serotonin from damaged enterochromaffincells in the gastrointestinal tract. Release of the neurotransmitterserotonin stimulates both afferent vagal nerve fibers (thus initiatingthe vomiting reflex) and serotonin receptors in the chemoreceptortrigger zone of the area postrema region of the brain. The anatomicalsite for this action of the benzamide derivatives, and whether suchaction is central (CNS), peripheral, or a combination thereof, remainsunresolved (See: Barnes et al., J. Pharm. Pharmacol. 40: 586-588, 1988).Cisapride, like the other benzamide derivatives may be an effectiveantiemetic agent based on its ability to modulate the activity ofserotonin at the 5HT3 receptor.

A second prominent action of the benzamide derivatives is in augmentinggastrointestinal smooth muscle activity from the esophagus through theproximal small bowel, thus accelerating esophageal and small intestinaltransit as well as facilitating gastric emptying and increasing loweresophageal sphincter tone (See: Decktor et al., Eur. J. Pharmacol. 147:313-316, 1988). Although the benzamide derivatives are not cholinergicreceptor agonists per se, the aforementioned smooth muscle effects maybe blocked by muscarinic receptor blocking agents such as atropine orneuronal transmission inhibitors of the tetrodotoxin type which affectsodium channels (See: Fernandez and Massingham, Life Sci. 36: 1-14,1985). Similar blocking activity has been reported for the contractileeffects of serotonin in the small intestine (See: Craig and Clarke,Brit. J. Pharmacol. 96: 247P, 1989). It is currently believed that theprimary smooth muscle effects of the benzamide derivatives are theresult of an agonist action upon a new class of serotonin receptorsreferred to as 5HT4 receptors which are located on interneurons in themyenteric plexus of the gut wall (See Clarke et al., Trends inPharmacological Sciences 10: 385-386, 1989 and Dumuis et al., N. S.Arch. Pharmacol. 340: 403-410, 1989). Activation of these receptorssubsequently enhances the release of acetylcholine from parasympatheticnerve terminals located near surrounding smooth muscle fibers, and it isthe combination of acetylcholine with its receptors on smooth musclemembranes which is the actual trigger for muscle contraction.

Racemic cisapride possesses similar properties to metoclopramide exceptthat it lacks dopamine receptor blocking activity (See: Reyntjens etal., Curr. Therap. Res. 36: 1045-1046, 1984) and enhances motility inthe colon as well as in the upper portions of the alimentary tract (See:Milo, Curr. Therap. Res. 36: 1053-1062, 1984). The colonic effects,however, may not be completely blocked by atropine and may represent, atleast in part, a direct action of the drug (See: Schuurkes et al., J.Pharmacol Exp. Ther. 234: 775-783, 1985). Using cultured mouse embryocolliculi neurons and cAMP generation as an endpoint for designating5HT4 activity, the EC50 concentration of racemic cisapride was 7×10⁻⁸ M(See: Dumuis et al., N. S. Arch. Pharmacol. 340: 403-410, 1989). Drugsof this class do not affect gastric acid secretion and have variableeffects upon colonic motility (See: Reyntjens et al., Curr. Therap. Res.36: 1045-1046, 1984 and Milo, Curr. Therap. Res. 36: 1053-1062, 1984).

The racemic mixture of cisapride is presently used primarily to treatgastro-esophageal reflux disease. This disease is characterized as thebackward flow of the stomach contents into the esophagus. One of themost important factors in the pathogenesis of gastro-esophageal refluxdisease is a reduction in the pressure barrier due to the failure of thelower esophageal sphincter. Failure of the lower esophageal sphinctercan arise due to a low basal pressure, sphincter relaxation, or to anon-compensated increase in intragastric pressure. Other factors in thepathogenesis of the disease are delayed gastric emptying, insufficientesophageal clearing due to impaired peristalsis and the corrosive natureof the reflux material which can damage esophageal mucosa. The racemicmixture of cisapride is thought to strengthen the anti-reflux barrierand improve esophageal clearance by increasing the lower esophagealsphincter pressure and enhancing peristaltic contractions.

Because of its activity as a prokinetic agent, the racemic mixture ofcisapride may also be useful to treat dyspepsia, gastroparesis,constipation, post-operative ileus, and intestinal pseudo-obstruction.Dyspepsia is a condition characterized by an impairment of the power orfunction of digestion that can arise as a symptom of a primarygastrointestinal dysfunction or as a complication due to other disorderssuch as appendicitis, gallbladder disturbances, or malnutrition.Gastroparesis is a paralysis of the stomach brought about by a motorabnormality in the stomach or as a complication of diseases such asdiabetes, progressive systemic sclerosis, anorexia nervosa or myotonicdystrophy. Constipation is a condition characterized by infrequent ordifficult evacuation of feces resulting from conditions such as lack ofintestinal muscle tone or intestinal spasticity. Post-operative ileus isan obstruction in the intestine due to a disruption in muscle tonefollowing surgery. Intestinal pseudo-obstruction is a conditioncharacterized by constipation, colicky pain, and vomiting, but withoutevidence of physical obstruction.

The administration of the racemic mixture of cisapride to a human hasbeen found to cause adverse effects including, tachycardia, CNSdisorders, increased systolic pressure, interactions with other drugs,diarrhea, and abdominal cramping. Further, it has been reported thatintravenous administration of racemic cisapride demonstrates theoccurrence of additional adverse (side) effects not experienced afteroral administration of racemic cisapride. Stacher et al. DigestiveDiseases and Sciences 32(11): 1223-1230 (1987).

Racemic cisapride is almost completely absorbed after oraladministration to humans, but the bioavailability of the parent compoundis only 40-50%, due to rapid first pass metabolism in the liver (See:Van Peer et al., in Progress in the Treatment of GastrointestinalMotility Disorders: The Role of Cisapride. Proceedings of a Symposium inFrankfurt. November 1986. Johnson A. G. and Lux, G. eds. ExcerptaMedica, Amsterdam, pp. 23-29 (1988). More than 90% of a dose ofcisapride is metabolized mainly by oxidative N-dealkylation at thepiperidine nitrogen or by aromatic hydroxylation occurring on either the4-fluorophenoxy or benzamide rings. Short duration of action, as seenwith racemic cisapride, can often be associated with erraticpharmacological effects following oral administration of compounds.

Thus, it would be particularly desirable to find a compound with theadvantages of the racemic mixture of cisapride which would not have theaforementioned disadvantages.

SUMMARY OF THE INVENTION

It has now been discovered that novel compositions of matter containingthe optically pure (+) isomer of cisapride are useful in treatinggastro-esophageal reflux disease while substantially reducing adverseeffects associated with the administration of the racemic mixture ofcisapride, including but not limited to diarrhea, abdominal cramping andelevations of blood pressure and heart rate. It has also been discoveredthat optically pure (+) cisapride is an effective antiemetic agent,useful as an adjunctive therapy in cancer treatment to alleviate nauseaand vomiting induced by chemo- or radio-therapeutics, whilesubstantially reducing the above-described adverse effects associatedwith the administration of the racemic mixture of cisapride. It has alsobeen discovered that these novel compositions of matter containingoptically pure (+) cisapride are useful in treating dyspepsia and suchother conditions as may be related to the activity of (+) cisapride as aprokinetic agent, e.g., gastroparesis, constipation, post-operativeileus, and intestinal pseudo-obstruction, while substantially reducingthe above-described adverse effects associated with the administrationof the racemic mixture of cisapride. The present invention also includesmethods for treating the above-described conditions in a human whilesubstantially reducing adverse effects that are associated with theracemic mixture of cisapride, by administering the optically pure (+)isomer of cisapride to said human. Furthermore, the present inventionalso includes methods and compositions which demonstrate an improvedbioavailability over racemic cisapride irrespective of the mode ofadministration.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a method of treating gastro-esophagealreflux disease in a human, while substantially reducing the concomitantliability of adverse effects associated with the administration ofracemic cisapride, which comprises administering to a human in need ofsuch treatment, an amount of (+) cisapride, or a pharmaceuticallyacceptable salt thereof, substantially free of its (-) stereoisomer,said amount being sufficient to alleviate said reflux disease, butinsufficient to cause said adverse effects associated with the racemicmixture of cisapride.

The present invention also encompasses a composition for the treatmentof a human suffering from gastro-esophageal reflux disease, whichcomprises an amount of (+) cisapride, or a pharmaceutically acceptablesalt thereof, substantially free of its (-) stereoisomer, said amountbeing sufficient to alleviate said reflux disease, but insufficient tocause adverse effects associated with racemic cisapride.

The present invention further encompasses a method of eliciting anantiemetic effect in a human, while substantially reducing theconcomitant liability of adverse effects associated with theadministration of racemic cisapride, which comprises administering to ahuman in need of such antiemetic therapy, an amount of (+) cisapride, ora pharmaceutically acceptable salt thereof, substantially free of its(-) stereoisomer, said amount being sufficient to alleviate nausea andvomiting but insufficient to cause adverse effects associated with theadministration of racemic cisapride.

In addition, the present invention encompasses an antiemetic compositionfor the treatment of a human in need of antiemetic therapy, whichcomprises an amount of (+) cisapride, or a pharmaceutically acceptablesalt thereof, substantially free of its (-) stereoisomer, said amountbeing sufficient to alleviate nausea and vomiting but insufficient tocause adverse effects associated with the administration of racemiccisapride.

A further aspect of the present invention includes a method of treatinga condition caused by gastrointestinal motility dysfunction in a human,while substantially reducing the concomitant liability of adverseeffects associated with the administration of racemic cisapride, whichcomprises administering to a human in need of treatment forgastrointestinal motility dysfunction, an amount of (+) cisapride, or apharmaceutically acceptable salt thereof, substantially free of its (-)stereoisomer, said amount being sufficient to alleviate said conditionbut insufficient to cause adverse effects associated with theadministration of racemic cisapride. Conditions caused bygastrointestinal motility dysfunction in a human include, but are notlimited to, dyspepsia, gastroparesis, constipation, post-operativeileus, and intestinal pseudo-obstruction,

Furthermore, the present invention includes a composition for treating acondition caused by gastrointestinal motility dysfunction in a human,which comprises an amount of (+) cisapride, or a pharmaceuticallyacceptable salt; thereof, substantially free of its (-) stereoisomer,said amount being sufficient to alleviate said condition caused bygastrointestinal motility dysfunction, but insufficient to cause adverseeffects associated with the administration of racemic cisapride.

The present invention encompasses a novel composition of mattercomprising (+) cisapride or a pharmaceutically acceptable salt thereof,substantially free of its (-) stereoisomer, wherein said compositionprovides a higher bioavailability of the active compound than does theracemic mixture. The bioavailability of (+) cisapride is found to behigher than that of racemic cisapride irrespective of the mode ofadministration. Further, these novel compositions are used to treat avariety of disorders, as described above, while substantially reducingadverse effects which are caused by the administration of racemiccisapride. These novel compositions may optionally contain apharmaceutically acceptable carrier or combinations thereof as describedbelow.

The increased bioavailability of (+) cisapride allows for a moreeffective pharmacodynamic profile than racemic cisapride and a moreeffective management of the disease being treated. For example, a moreeffective management of disorders is achieved with the administration of(+) cisapride, since dosing frequency can be reduced. This wouldfacilitate, e.g., overnight treatment while the patient is asleep.Similarly, a lower dose frequency is beneficial when (+) cisapride isused prophylactically or as a treatment for emesis in cancer patients.

Therefore, the present invention further encompasses a method fortreating gastro-esophageal reflux disease in a human while achievinghigher bioavailability than racemic cisapride which comprisesadministering to a human in need of treatment from such a disorder, anamount of (+) cisapride, or a pharmaceutically acceptable salt thereof,substantially free of its (-) stereoisomer, said amount being sufficientto alleviate said reflux disease and said amount having increasedbioavailability over the racemic mixture of cisapride.

The present invention also encompasses a method of eliciting anantiemetic effect in a human while achieving a higher bioavailabilitythan racemic cisapride which comprises administering to a human in needof antiemetic therapy, an amount of (+) cisapride, or a pharmaceuticallyacceptable salt thereof, substantially free of its (-) stereoisomer,said amount being sufficient to alleviate nausea and vomiting and saidamount having higher bioavailability than racemic cisapride.

The present invention further encompasses a method of treating acondition caused by gastro-intestinal motility dysfunction in a human,while achieving higher bioavailability than racemic cisapride, whichcomprises administering to a human in need of treatment forgastrointestinal motility dysfunction, an amount of (+) cisapride, or apharmaceutically acceptable salt thereof, substantially free of its (-)stereoisomer, said amount being sufficient to alleviate said conditionand said amount having a higher bioavailability than racemic cisapride.

In addition, the present invention encompasses methods for treating theabove-described conditions, comprising administering to a human in needof treatment for such a condition, an amount of (+) cisapride, or apharmaceutically acceptable salt thereof, substantially free of its (-)stereoisomer, said amount having increased bioavailability over theracemic mixture and being sufficient to alleviate said condition butbeing insufficient to cause adverse effects associated with racemiccisapride.

The observation that cisapride enters the central nervous system andbinds to 5HT4 receptors indicates that cisapride may havecentrally-mediated effects. As was shown by Dumuis et al., N.S. Arch.Pharmacol. 340: 403-410, 1989, cisapride is a potent ligand at 5HT4receptors, and these receptors are located in several areas of thecentral nervous system. Modulation of serotonergic systems has a varietyof behavioral effects. Cisapride, therefore, could be therapeuticallyuseful in the treatment of: 1) cognitive disorders, including but notlimited to Alzheimer's disease; 2) behavioral disorders, including butnot limited to schizophrenia, mania, obsessive-compulsive disorder, andpsychoactive substance use disorders; 3) mood disorders, including butnot limited to depression and anxiety; and 4) disorders of control ofautonomic function, including but not limited to essential hypertensionand sleep disorders.

The available racemic mixture of cisapride (i.e., a 1:1 racemic mixtureof the two cis enantiomers) possesses prokinetic and antiemeticactivity, and provides therapy and a reduction of symptoms in a varietyof conditions and disorders related to gastrointestinal motilitydysfunction; however, this racemic mixture, while offering theexpectation of efficacy, causes adverse effects and has a relativelyshort duration of action. Utilizing the substantially optically pure oroptically pure isomer of (+) cisapride results in clearer dose relateddefinitions of efficacy, diminished adverse effects, and accordingly, animproved therapeutic index as well as a higher bioavailability. It istherefore more desirable to use the (+) isomer of cisapride than toadminister the racemic mixture.

The term "bioavailability" refers to the rate, extent, and duration withwhich an active drug or metabolite enters and remains in the generalcirculation, thereby permitting access to the site of action. Higherbioavailability may be achieved by, e.g., increasing the drug's durationof action.

The term "adverse effects" includes, but is not limited to,gastrointestinal disorders such as diarrhea, abdominal cramping, andabdominal grumbling; tiredness; headache; increased systolic pressure;increased heart rate; neurological and CNS disorders; and interaction ofcisapride with other drugs given concurrently such as digoxin, diazepam,ethanol, acenocoumarol, cimetidine, ranitidine, paracetamol, andpropranolol.

The term "substantially free of its (-) stereoisomer" as used hereinmeans that the compositions contain at least 90% by weight of (+)cisapride and 10% by weight or less of (-) cisapride. In a morepreferred embodiment the term "substantially free of the (-)stereoisomer" means that the composition contains at least 99% by weightof (+) cisapride, and 1% or less of (-) cisapride. In a most preferredembodiment, the term "substantially free of its (-) stereoisomer" asused herein means that the composition contains greater than 99% byweight of (+) cisapride. These percentages are based upon the totalamount of cisapride in the composition. The terms "substantiallyoptically pure (+) isomer of cisapride" or "substantially optically pure(+) cisapride" and "optically pure (+) isomer of cisapride" and"optically pure (+) cisapride" are encompassed by the above-describedamounts.

The term "gastro-esophageal reflux disease" as used herein means theincidence of, and the symptoms of, those conditions causing the backwardflow of the stomach contents into the esophagus.

The terms "eliciting an antiemetic effect" and "antiemetic therapy" asused herein mean providing relief from or preventing the symptoms ofnausea and vomiting induced spontaneously or associated with emetogeniccancer chemotherapy or irradiation therapy.

The term "treating a condition caused by gastrointestinal motilitydysfunction" as used herein means treating the symptoms and conditionsassociated with this disorder which include, but are not limited to,dyspepsia, gastroparesis, constipation, post-operative ileus, andintestinal pseudo-obstruction.

The term "prokinetic" as used herein means the enhancement ofperistalsis in, and thus the movement through the gastrointestinaltract.

The term "dyspepsia" as used herein means a condition characterized byan impairment of the power or function of digestion that can arise as asymptom of a primary gastrointestinal dysfunction or as a complicationdue to other disorders such as appendicitis, gallbladder disturbances,or malnutrition.

The term "gastroparesis" as used herein means a paralysis of the stomachbrought about by a motor abnormality in the stomach or as a complicationof diseases such as diabetes, progressive systemic sclerosis, anorexianervosa, or myotonic dystrophy.

The term "constipation" as used herein means a condition characterizedby infrequent or difficult evacuation of feces resulting from conditionssuch as lack of intestinal muscle tone or intestinal spasticity.

The term "post-operative ileus" as used herein means an obstruction inthe intestine due to a disruption in muscle tone following surgery.

The term "intestinal pseudo-obstruction" as used herein means acondition characterized by constipation, colicky pain, and vomiting, butwithout evidence of physical obstruction.

The chemical synthesis of the racemic mixture of cisapride can beperformed by the method described in European Patent Application No.0,076,530 A2 published Apr. 13, 1983, U.S. Pat. Nos. 4,962,115 and5,057,525 and in Van Daele et al., Drug Development Res. 8: 225-232(1986), the disclosures of which are incorporated herein by reference.The (+) isomer of cisapride may be obtained from its racemic mixture byresolution of the enantiomers using conventional means such as from anoptically active resolving acid. See, for example, "Enantiomers,Racemates and Resolutions," by J. Jacques, A. Collet, and S. H. Wilen,(Wiley-Intenscience, New York, 1981); S. H. Wilen, A. Collet, and J.Jacques, Tetrahedron, 33, 2725 (1977); and "Stereochemistry of CarbonCompounds, by E. L. Eliel (McGraw-Hill, N.Y., 1962) and S. H. Wilen,page 268, in "Tables of Resolving Agents and Optical Resolutions" (E. L.Eliel, Ed. Univ. of Notre Dame Press, Notre Dame, Ind., 1972).Furthermore, the optically pure (+) isomer of cisapride can be preparedfrom the racemic mixture by enzymatic biocatalytic resolution. See, forexample, U.S. Pat. Nos. 5,057,427 and 5,077,217, the disclosures ofwhich are incorporated by reference.

The magnitude of a prophylactic or therapeutic dose of (+) cisapride inthe acute or chronic management of diseases and/or disorders describedherein will vary with the severity of the condition to be treated, andthe route of administration. The dose, and perhaps the dose frequency,will also vary according to the age, body weight, and response of theindividual patient. In general, the total daily dose range for (+)cisapride, for the conditions described herein, is from about 1 mg toabout 200 mg, in single or divided doses. Preferably, a daily dose rangeshould be between about 5 mg to about 100 mg, in single or divideddoses, while most preferably, a daily dose range should be between about5 mg to about 75 mg, in single or divided doses. It is preferred thatthe doses are administered from 1 to 4 times a day. In managing thepatient, the therapy should be initiated at a lower dose, perhaps about5 mg to about 10 mg, and increased up to about 50 mg or higher dependingon the patient's global response. It is further recommended thatchildren,, and patients over 65 years, and those with impaired renal orhepatic function, initially receive low doses, and that they be titratedbased on individual response(s) and blood level(s). It may be necessaryto use dosages outside these ranges in some cases as will be apparent tothose skilled in the art. Further, it is noted that the clinician ortreating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with individual patient response. Theterms "an amount sufficient to alleviate said reflux disease, butinsufficient to cause adverse effects", "an amount sufficient toalleviate nausea and vomiting but insufficient to cause adverseeffects", and "an amount sufficient to alleviate said condition causedby gastrointestinal motility dysfunction, but insufficient to causeadverse effects" are encompassed by the above-described dosage amountsand dose frequency schedule.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of cisapride. For example, oral,rectal, parenteral (subcutaneous, intramuscular, intravenous),transdermal, and like forms of administration may be employed. Dosageforms include tablets, troches, dispersions, suspensions, solutions,capsules, patches, and the like.

The pharmaceutical compositions of the present invention comprise (+)cisapride as the active ingredient, or a pharmaceutically acceptablesalt thereof, and may also contain a pharmaceutically acceptablecarrier, and optionally, other therapeutic ingredients.

The term "pharmaceutically acceptable salts" or "a pharmaceuticallyacceptable salt thereof" refer to salts prepared from pharmaceuticallyacceptable non-toxic acids or bases including inorganic acids and basesand organic acids and bases. Since the compound of the present inventionis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids. Suitable pharmaceutically acceptable acid additionsalts for the compound of the present invention include acetic,benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaricacid, p-toluenesulfonic, and the like. Preferred acid addition salts arethe chloride and sulfate salts. In the most preferred embodiment, (+)cisapride is administered as the free base.

The compositions of the present invention include compositions such assuspensions., solutions and elixirs; aerosols; or carriers such asstarches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders, disintegrating agents, and the like, in thecase of oral solid preparations (such as powders, capsules, and tablets)with the oral solid preparations being preferred over the oral liquidpreparations. A preferred oral solid preparation is capsules. The mostpreferred oral solid preparation is tablets.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are employed. If desired, tablets may be coatedby standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofthe present invention may also be administered by controlled releasemeans and/or delivery devices such as those described in U.S. Pat. Nos.:3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, thedisclosures of which are hereby incorporated by reference.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets, or tablets, or aerosols sprays, each containing a predeterminedamount of the active ingredient, as a powder or granules, or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Suchcompositions may be prepared by any of the methods of pharmacy, but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation.

For example, a tablet may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding, in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet contains from about 1 mg to about100 mg of the active ingredient, and each cachet or capsule containsfrom about 1 mg to about 50 mg of the active ingredient. Mostpreferably, the tablet, cachet or capsule contains either one of threedosages, i.e., about 5 mg, about 10 mg or about 25 mg of the activeingredient.

The invention is further defined by reference to the following examples,describing in detail the preparation of the compound and thecompositions of the present invention, as well as their utility. It willbe apparent to those skilled in the art that many modifications, both tomaterials and methods, may be practiced without departing from thepurpose and interest of this invention.

EXAMPLES Example 1

Determination of Efficacy

The relative activities of optically pure (-), (+), and racemiccisapride are determined by a pharmacological study in dogs. Evaluationof these compounds is based on their relative potencies in a test tomeasure gastric emptying as an index of prokinetic activity in thestomach. The compounds are dissolved or suspended in 0.5%methylcellulose and administered at varying doses via an indwellinggastric fistula to adult beagle flogs. The compounds are given 60minutes prior to the administration via fistula of a liquid test mealcontaining the dye phenol red. The gastric contents are collected 5minutes later via gravity drainage through the fistula. Gastric emptyingduring this period may be calculated according to the formula of Debas(See: Fitzpatrick et al., J. Pharmacol. Exp. Ther. 254: 450-455, 1990)which takes into account both the volume of meal collected and theconcentration of the dye. The relative potencies of (-) cisapride, (+)cisapride, and racemic cisapride are assessed via standard parallel lineassays.

Example 2

Bioavailability

A single dose of test substance or vehicle is administered to malebeagle dogs either intravenously as a bolus over one minute using a 23ga butterfly needle into the saphenous vein, or as a single dose viaoral gavage. 2.0 ml of whole blood is collected from each dog prior toand at intervals of 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 9, 12, and 24 hoursfollowing the intravenous or oral administration of (+), (-), or racemiccisapride. The dogs are placed in sling-restraint prior toadministration of test substance and are transferred to metabolic cagesfollowing collection of the 0.083 hour blood sample. All blood samplesare collected from an angiocatheter placed in a cephalic vein on themorning of the experiment.

The blood is drawn into a 3 cc syringe. The first 1.0-2.0 ml of blood isdiscarded. The next 2.0 ml of whole blood is quickly transferred to aheparinized tube. The heparinized tubes are kept on ice until the bloodis added. After adding the blood to the tube, the contents of the tubeare mixed and centrifuged to obtain plasma. The plasma is carefullydecanted and transferred to a test tube labelled with: the animalnumber, the dose of test substance administered, the route ofadministration, the date of administration, and the time of bloodcollection. The tubes are stored at -20° C. until analysis.

Analysis of the concentration of (+), (-), or racemic cisapride in eachplasma sample is determined using high performance liquidchromatography. For each test substance the plasma concentration vs.sample time is plotted for both routes of administration. The oralbioavailability of each test substance is determined by comparing theC_(max) and AUC for the oral route of administration versus those forthe i.v. route. The t_(1/2) for each test substance by both routes iscalculated as an indicator of duration of action.

Example 3

5HT3 Receptor Binding

The affinity of compounds for the 5HT3 receptor is assessed via aradioligand binding assay using animal membranes that are rich in suchreceptors, e.g., those derived from the cerebral cortex of rat brains(See: Fitzpatrick et al., J. Pharmacol. Exp. Ther. 254: 450455, 1990).Plasma membranes from the animal source are equilibrated in test tubeswith solutions containing a radioactive 5HT3 receptor ligand and variousconcentrations of (-) cisapride, (+) cisapride or racemic cisapride.After incubation for 30 minutes, the membranes are isolated on a filterand the degree of inhibition of radioactive ligand binding isdetermined. Based on the results obtained, the concentration of eachcompound which inhibits ligand binding by 50% (the IC50) is calculated.

Example 4

5HT4 Receptor Agonist Activity

Agonist activity at 5HT4 receptor sites is assessed using an assay basedon the ability of active compounds to increase cyclic AMP production inmouse embryo colloculi neurones grown in tissue culture (See: Dumuis etal., N. S. Arch. Pharmacol. 340: 403-410, 1989). (-) cisapride, (+)cisapride and racemic cisapride, at varying concentrations, areincubated with these cells for 10 minutes in the presence of the cAMPprecursor substance, ATP. At the end of this period, the degree offormation of cAMP is assessed. The concentration of agonist compoundrequired to increase the formation of cAMP by 50% of the maximalpossible (the EC50) is then calculated.

Example 5

Determination of Cardiovascular Effects

Unanesthetized spontaneously hypertensive rats (SHR) with systolic bloodpressures ranging between 180 and 220 mm Hg are used. Blood pressure isrecorded indirectly in a temperature-controlled environment before, and1, 2, and 4 hours after, the test substance is administered p.o. Thetest substances are racemic, (-) and (+) cisapride. Increases insystolic blood pressure by more than 10% (>10) at any two of theaforementioned three consecutive time points is considered significant.In the same spontaneously hypertensive rats, heart rate is recorded by acardiograph immediately after the blood pressure recordings. An increasein heart rate greater than 20 percent (>20) from pre-treatment controlreadings is considered significant.

Example 6

Colonic Propulsive Motility

The purpose of this study is to demonstrate and characterize thepharmacological effects of experimental compounds on colonic propulsivemotility in the mouse. The test is based on the reflex expulsion of aglass bead from the distal colon, which is indicative of drug effects onthe reflex arc. This test is useful in evaluating whether diarrhea is aside effect, and may provide evidence of compounds lacking this effect.

Female albino Swiss CD-1 mice, 18-24 grams, are obtained. They arehoused in groups of 5-10 in plastic cages maintained in aclimate-controlled room with water and food available ad libitum. Miceare fasted for one hour prior to oral administration of test compounds.Mice are administered drug (calculated as base weight) or vehicle by theappropriate route. Control animals receive a similar quantity of theappropriate vehicle.

The experimental compound is administered orally at the appropriatedose(s) and followed 30 minutes later by the insertion of a single 3 mmglass bead 2 cm into the distal colon of each mouse. Mice are marked foridentification and placed in large glass beakers for observation. Thetime required for expulsion of the bead is noted for each mouse with acut-off period of 30 minutes. Mice not expelling the bead by that timeare sacrificed in a carbon dioxide chamber and necropsied to confirm thepresence of the bead within the lumen of the colon. Mice for which beadlocalization within the lumen could not be confirmed (perforation) werenot included in the results. Mice receiving vehicle usually expel thebead in a range of 4-6 minutes. Experimental compounds are racemiccisapride, (+) cisapride and (-) cisapride.

Data are analyzed for difference from vehicle control using two-wayanalysis of variance and Fisher's least significant differencecomparision (LSD) test. ED₅₀ s (the dose causing a 50% prolongation oftime for expulsion) for compounds having significant activity arecalculated using regression analysis.

Example 7

Gastric Emptying

Gastric emptying is evaluated by determining the emptying of 1 mmpolystyrene beads from the stomach of fasted rats. Evaluation of gastricemptying in the rat is an important pharamacological parameter. Druginduced inhibition of gastric emptying in the rat is often acharacteristic of compounds producing emesis or other gastrointestinalsymptoms in other species. Drugs speeding gastric emptying can be usefultherapeutically for a number of gastrointestinal dysfunctions. This testis sensitive to the inhibition of gastric emptying produced byanticholinergics and some centrally acting compounds, and to theprokinetic activity of compounds such as metoclopramide, domperidone andracemic cisapride.

Male or female Sprague-Dawley rats, 80-150 grams, are obtained andquarantined for 7 days. They are housed individually on wire with wateravailable ad libitum. Food is withheld 24 hours prior to the study. Ratsare administered drug (calculated as base weight) by the appropriateroute.

Rats are administered (+), (-), or racemic cisapride by the appropriateroute. 30 or 60 minutes later, ten 1 mm polystyrene pellets areadministered by gavage. For tests evaluating inhibition of gastricemptying, rats are sacrificed 3 hours after pellet administration. Totest for potential augmentation of emptying, rats are sacrificed 30minutes after pellet administration. Rats are sacrificed in a carbondioxide chamber, and the stomachs are removed. The number of the pelletsremaining in the stomach are counted In control studies, 90% of pelletsare still in the stomach after 30 minutes, and fewer than 10% of pelletsare in the stomach after 3 hours.

Data are analyzed for difference from vehicle control using two-wayanalysis of variance and Fisher's least significant differencecomparision (LSD) test. ED₅₀ s (the dose causing a 50% prolongation oftime for expulsion) for compounds having significant activity arecalculated using regression analysis.

Example 8

Central Nervous System Effects

The effects of racemic and optically pure cisapride on memory can betested using the method described by Forster et al., Drug DevelopmentResearch, 11: 97-106 (1987). In this technique, pharmacologic effects ofdrugs on memory in mice are tested using a "discriminated escape"paradigm. Groups of mice are designated for vehicle and drug treatment,and each mouse is trained to enter the correct goal arm of a T-maze toescape an 0.8 mA foot shock delivered through the floor of theapparatus. The mice are dosed with vehicle or test compound during thetraining period.

The mice are initially given a preference trial in which entry to eithergoal arm will result in termination of foot shock, but they are trainedto escape the shock via the arm opposite their preference in allsubsequent trials. Mice are trained ("minimal training") until alearning criterion of two consecutive correct choices is met.

One week after training, all mice are tested for retention of thediscrimination. The measure of retention is the percentage of correctchoice trials, i.e., those in which the mouse enters the arm of the mazein which he does not receive a foot shock. Retention of discriminationis compared for the groups of mice that have been dosed, respectively,with (-) cisapride, (+) cisapride, racemic cisapride, and vehicle.

Effects of racemic and optically pure cisapride on sleep can be testedusing electroencephalographic analysis. Groups of rats or dogs areprepared for electroencephalographic recordings by implanting cranialelectrodes under general anesthesia, and then connecting theseelectrodes to an electroencephalic recording device after the effects ofthe anesthesia have worn off. These recordings are made continuously,and are used to classify the sleep state of the animal. Sleep states areclassified as either "awake," "slow-wave sleep," or "REM sleep." Thepercentage of each of the sleep states following administration ofplacebo, cisapride isomers, or racemate is compared to evaluate thesleep-regulating effect of the tested drug.

Blockade of the conditioned avoidance response (CAR) can be used todemonstrate the ability of racemic and optically pure cisapride to treatthe symptoms of schizophrenia. This testing procedure employs rats thatare trained to avoid a foot shock by pressing a lever at the start of atest period. The start of the test period is signaled by a non-noxiousstimulus (light or buzzer). Animals that are fully trained in thisprocedure will avoid the foot shock more than 90% of the time. Compoundsthat are effective antipsychotics will block this conditioned avoidanceresponse. Thus, (+), (-), and racemic cisapride are tested byadministering fixed doses of test and reference compounds to trainedrats and then determining their relative effects on conditionedavoidance.

Racemic and optically pure cisapride are tested for antidepressantactivity using the mouse tail suspension test (Steru et al.,Psychopharmacology 85: 367-370, 1985). A fixed dose of (+), (-), orracemic cisapride or a reference drug is administered to a mouse, andthe mouse is suspended about 15 cm above the table from a hook that istaped to the tail. The animal's movements are recorded on a polygraph.Mice typically struggle for a few minutes, and then bouts of movementare interspersed with periods of immobility ("behavioral despair"). Adecrease in the total duration of immobility during a standard testsession signifies potential antidepressant activity of the testcompound.

Racemic and optically pure cisapride are tested for effects onpsychoactive substance use disorders by administering test or referencecompound to laboratory animals, e.g., rats, that are trained to press alever in anticipation of receiving one of a variety of psychoactivesubstances ("drug self-administration"). Separate animals that have beentrained to self-administer cocaine, alcohol, and morphine are employedin this study. Fixed ratios and progressive ratios are used in settingthe amount of lever pressing that is required for the animal to receivethe substance. (+), (-), and racemic cisapride are administered at fixeddoses before the standard self-administration session. A decrease in thenumber of self-administrations or a reduction in the lever press/rewardratio indicates that the test compound has utility in treatingpsychoactive substance use disorders.

Example 9

Oral Formulation

    ______________________________________                                        Tablets                                                                                          Quantity per Tablet in mg.                                 Formula            A        B      C                                          ______________________________________                                        Active Ingredient  5.0      10.0   25.0                                       (+) cisapride                                                                 Lactose BP         62.0     57.0   42.0                                       Starch BP          20.0     20.0   20.0                                       Microcrystalline Cellulose                                                                       10.0     10.0   10.0                                       Hydrogenated Vegetable Oil                                                                       1.5      1.5    1.5                                        Polyvinylpyrrolidinone                                                                           1.5      1.5    1.5                                        Compression Weight 100.0    100.0  100.0                                      ______________________________________                                    

The active ingredient, (+) cisapride, is sieved through a suitable sieveand blended with the lactose until a uniform blend is formed. Suitablevolumes of water are added and the powders are granulated. After drying,the granules are then screened and blended with the remainingexcipients. The resulting granules are then compressed into tablets ofdesired shape. Tablets of other strengths may be prepared by alteringthe ratio of active ingredient to the excipient(s) or the compressionweight.

What is claimed is:
 1. A method of eliciting an antiemetic effect in ahuman, comprising administering to said human a therapeuticallyeffective amount of (+) cisapride, or a pharmaceutically acceptable saltthereof, substantially free of its (-) stereoisomer.
 2. A method ofeliciting an antiemetic effect in a human while achieving a higherbioavailability than is attainable with racemic cisapride, comprisingadministering to said human a therapeutically effective amount of (+)cisapride, or a pharmaceutically acceptable salt thereof, substantiallyfree of its (-) stereoisomer.
 3. The method of claims 1 or 2 wherein (+)cisapride is administered by intravenous infusion, transdermal delivery,or orally as a tablet, a capsule, or a liquid suspension.
 4. The methodof claim 3 wherein the amount of (+) cisapride or a pharmaceuticallyacceptable salt thereof administered is from about 1 mg to about 200 mgper day.
 5. The method of claim 4 wherein the amount administered isfrom about 5 mg to about 100 mg per day.
 6. The method of claim 5wherein the amount administered is from about 5 mg to about 75 mg perday.
 7. The method of claim 4 wherein said amount is administered in oneto four unit doses per day.
 8. The method of claim 7 wherein said amountis administered in one to two unit doses per day.
 9. The method ofclaims 1 or 2 wherein the amount of (+) cisapride or a pharmaceuticallyacceptable salt thereof is greater than approximately 90% by weight ofthe total weight of cisapride.
 10. The method of claims 1 or 2 whereinthe amount of said (+) cisapride or a pharmaceutically acceptable saltthereof, substantially free of its (-) stereoisomer is administeredtogether with a pharmaceutically acceptable carrier.